title: ABCA12 maintains the epidermal lipid permeability barrier by facilitating formation of ceramide linoleic esters.
abstract: Harlequin ichthyosis is a congenital scaling syndrome of the skin in which affected infants have epidermal hyperkeratosis and a defective permeability barrier. Mutations in the gene encoding a member of the ABCA transporter family, ABCA12, have been linked to harlequin ichthyosis, but the molecular function of the protein is unknown. To investigate the activity of ABCA12, we generated Abca12 null mice and analyzed the impact on skin function and lipid content. Abca12-/- mice are born with a thickened epidermis and die shortly after birth, as water rapidly evaporates from their skin. In vivo skin proliferation measurements suggest a lack of desquamation of the skin cells, rather than enhanced proliferation of basal layer keratinocytes, accounts for the 5-fold thickening of the Abca12-/- stratum corneum. Electron microscopy revealed a loss of the lamellar permeability barrier in Abca12-/- skin. This was associated with a profound reduction in skin linoleic esters of long-chain omega-hydroxyceramides and a corresponding increase in their glucosyl ceramide precursors. Because omega-hydroxyceramides are required for the barrier function of the skin, these results establish that ABCA12 activity is required for the generation of long-chain ceramide esters that are essential for the development of normal skin structure and function.
authors.affiliation: Lipid Metabolism Unit, Department of Medicine, Center for Computational & Integrative Biology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.
authors.forename: Ying
authors.initials: Y
authors.lastname: Zuo
authors.forename: Debbie Z
authors.initials: DZ
authors.lastname: Zhuang
authors.forename: Rong
authors.initials: R
authors.lastname: Han
authors.forename: Giorgis
authors.initials: G
authors.lastname: Isaac
authors.forename: Jennifer J
authors.initials: JJ
authors.lastname: Tobin
authors.forename: Mary
authors.initials: M
authors.lastname: McKee
authors.forename: Ruth
authors.initials: R
authors.lastname: Welti
authors.forename: Janice L
authors.initials: JL
authors.lastname: Brissette
authors.forename: Michael L
authors.initials: ML
authors.lastname: Fitzgerald
authors.forename: Mason W
authors.initials: MW
authors.lastname: Freeman
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000378:metabolism*; D000818:Animals; D049109:Cell Proliferation; D002518:Ceramides / Q000737:chemistry* / Q000378:metabolism; D004952:Esters / Q000737:chemistry*; D005838:Genotype; D005947:Glucose / Q000737:chemistry; D006579:Heterozygote; D019787:Linoleic Acid / Q000378:metabolism; D008055:Lipids / Q000737:chemistry*; D051379:Mice; D008854:Microscopy, Electron; D008957:Models, Genetic; D010539:Permeability; D012867:Skin / Q000378:metabolism
chemical_list: D018528:ATP-Binding Cassette Transporters; C532573:Abca12 protein, mouse; D002518:Ceramides; D004952:Esters; D008055:Lipids; D019787:Linoleic Acid; D005947:Glucose